Ketamine Induced Bladder Fibrosis Through MTDH/P38 MAPK/EMT Pathway.

Quan Zhu,Haozhen Li,Feng Han,Zhao Wang,Zhengyan Tang,Kaixuan Li

doi:10.3389/fphar.2021.743682

Quan Zhu, Haozhen Li + Show 4 more

Open Access

https://doi.org/10.3389/fphar.2021.743682

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Abstract

Purpose: Ketamine is an anesthetic in clinical, but it has also been used as an abusing drug due to its low price and hallucinogenic effects. It is proved that ketamine abusing would cause multiple system damage including the urinary system, which is called ketamine-induced cystitis (KIC). Bladder fibrosis is late stage in KIC and threaten abusers’ life. This study aimed to investigate the molecular mechanism of ketamine-induced bladder fibrosis. Methods: Female Sprague Dawley (SD) rats were randomly divided into 3 groups. 2 groups were treated with tail vein injection of ketamine (25 mg/kg/day, 50 mg/kg/day ketamine hydrochloride solution, respectively) for 12 weeks, whereas the control group was treated with normal saline solution. In each group, rat bladders were extracted and samples were examined for pathological and morphological alterations via hematoxylin and eosin (HE) staining, Masson’s trichrome staining and immunohistochemistry (IHC). SV-HUC-1 cells were treated with different concentrations of ketamine solution (0, 0.1, 0.5, 1 mmol/L). Rat bladder and SV-HUC-1 cells were extracted protein and RNA for Western blot and RT-PCR detection. Metadherin (MTDH) siRNAs and overexpression plasmids were used to knock down and overexpress the relative genes. P38 mitogen-activated protein kinase (MAPK) inhibitor was utilized to inhibit the MAPK pathway. Results: Rats in the ketamine group exhibited fibrosis compared to rats of the control group and fibrosis were also markedly upregulated in SV-HUC-1 cells after treated with ketamine, which were ketamine concentration-dependent. After treating with ketamine in SV-HUC-1 cells, there was an increase expression of MTDH, epithelial-mesenchymal transition (EMT) markers, P38 MAPK. MTDH knockdown would suppresses P38 MAPK/EMT pathway to inhibit fibrosis, however, MTDH overexpression could promote the pathway in SV-HUC-1 cells. Conclusion: In rats and SV-HUC-1 cells ketamine-treated models, MTDH can regulate EMT through the P38 MAPK pathway to regulate the process of bladder fibrosis.

Highlights

Ketamine, known as K powder, is an N–methyl–D–aspartate receptor antagonist (Paulis et al, 2020)
MTDH knockdown would suppresses P38 mitogen-activated protein kinase (MAPK)/ epithelial-mesenchymal transition (EMT) pathway to inhibit fibrosis, MTDH overexpression could promote the pathway in SV-HUC-1 cells
In rats and SV-HUC-1 cells ketamine-treated models, MTDH can regulate EMT through the P38 MAPK pathway to regulate the process of bladder fibrosis

Summary

Introduction

Known as K powder, is an N–methyl–D–aspartate receptor antagonist (Paulis et al, 2020). After long-term abusing of ketamine, it will damage the nervous and cardiovascular system, and damage the urinary system (Lee et al, 2017; Parkin et al, 2008). Scholars have reported that ketamine abusers are accompanied with severe lower urinary tract symptoms include frequency, dysuria, and hematuria, which was called ketamine-induced cystitis (KIC) clinically, bladder contracture were detected in severe cases (Lee et al, 2017; Parkin et al, 2008). Exploring the mechanism of ketamine-induced bladder fibrosis and delaying the progression of fibrosis is the vital therapy strategy of KIC and improve abusers’ life quality

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